Chronic skeletal pain is a frequent companion of aging. In large part this is because the mass, quality, and strength of human bone peaks at 25-30 years of age and declines thereafter. Thus, by the time most humans are 60, normally non-traumatic, low impact falls can result in fracture of the hip, wrist, or vertebrae. Fractures in oler individuals are frequently painful and heal at significantly slower rates than in the young. For example, in older individuals with hip fractures the fractured bone usually never fully heals, is frequently accompanied by chronic skeletal pain, and most individuals never fully recover their pre-fracture functional status and quality of life. Currently, disorders and aging of the bone are one of the most common causes of chronic pain and long-term physical disabilities in the United States and the world. In large part this is because we know very little about the mechanisms that drive age-related bone pain and bone healing. As a result, we have remarkably few mechanism-based analgesics to control the pain or anabolic therapies to accelerate healing following an age- related bone fracture. In the present proposal, our goal is to begin to develop a mechanism-based understanding of what drives age-related fracture pain and bone healing. To accomplish these goals we will use a model of bone fracture pain and bone healing in the young vs. old male and female mice. This model will allow us to simultaneously explore bone fracture healing, skeletal pain behaviors, changes in sensory and sympathetic nerve fiber expression and sprouting, and the bone microenvironment in the normal and fractured bone. Importantly, the mouse model closely mirrors the pain and bone healing that occurs in humans. A key aspect of the application is that we will be focusing on old mice, as with age there is a marked increase in bone fractures, skeletal pain, and bone fracture associated morbidity / mortality. Our specific aims are: 1) begin to elucidate the specific cells and factors that drive age-related fracture pain and bone healing; 2) determine the role that stromal cell factors, including nerve growth factor (NGF) and sclerostin, play in driving fracture pain and reducing fracture healing in the young vs. old bone. Our experience in working at the nerve / bone interface, the robust nature of the mouse bone fracture model, and the comparison of young vs. old offers a unique opportunity to increase our understanding of the mechanisms that drive age-related fracture pain / bone healing. If successful, these studies may help in the development of novel therapies that can more effectively treat age-related bone fractures. RELEVANCE: Skeletal pain is a frequent companion of aging. This project will focus on exploring the mechanisms that drive bone fracture pain / bone healing. If successful, this proposal has the potential to fundamentally transform our understanding of skeletal pain and how we treat and prevent age-related pain and bone fractures.